Most widely used vaccines are presently administered by systemic routes. In many cases these vaccines are effective in inducing systemic cell-mediated and systemic antibody responses, but are poor at inducing mucosal immunity in humans who have not had a previous mucosal infection by the causative organism. Many therapeutic biologicals (e.g., insulin, anti-tumor necrosis factor-alpha antibody, interferon-alpha, erythropoietin) are, like vaccines, delivered parenterally to avoid degradation by gastrointestinal secretions. A number of strategies are available to increase the efficacy of mucosally administered molecules. Common approaches involve the avoidance or modification of gastrointestinal secretions by the use of gastric inhibitors, protease and acid resistant films or encapsulation. Substrates used for oral delivery of these agents, which may have adjuvant activity, may include liposomes. The incorporation of molecules in liposomes or polymers can protect them from harmful digestive secretions.
The development of controlled release biologically-compatible systems using polymers has provided means for obtaining sustained release of biologically active agents. Recently, biodegradable polymeric microspheres have received much attention for the purpose of controlled release of antigens to eliminate the need for refrigeration, to reduce the number of immunization and to control dosage.
U.S. Pat. No. 4,744,933 also discloses the process of encapsulating bioactive materials. For example, the adjuvant effect of microspheres made of poly-DL-lactide-co-glycolide (DL-PLG) copolymer containing Staphylococcal enterotoxin B (SEB), when subcutaneously (sc) injected in to mice, was comparable to that of Freund's complete adjuvant (FCA). Ovalbumin (OVA) a poor immunogen when entrapped in DL PLG microparticles induced significantly higher levels of IgG antibodies in mice following primary immunization than did OVA in FCA.
U.S. Pat. No. 5,453,368 discloses a method for encapsulating a biological substance in biocompatible microcapsules. Additionally, it discloses the coating of the microcapsules with solution of a soluble organic polymer in an organic solvent.
U.S. Pat. No. 5,879,713 teaches the targeted delivery of small molecules such as nucleic acids and peptides. Delivery systems such as emulsions, liposomes and microspheres are widely regarded as protein carriers. As with other peptide and macro-molecular therapeutics or biologicals, the rate of release of antigens from biodegradable microspheres was shown to be dependent mainly on degradation of the polymeric matrix. Particulate delivery systems such as microspheres can also possess adjuvant activity when used as oral vehicles for antigens. Unfortunately, the current methods for generating microspheres, often made of lipids or polymers, require oil-water emulsion techniques that waste antigen or therapeutic protein and may alter the conformation of the encapsulated active agents, an important consideration in administration of polypeptides.